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Background: Flu-like symptoms (FLSs) and injection-site reactions (ISRs) have been reported with inter-feron beta treatments for multiple sclerosis (MS). We sought to obtain consensus on the characteristics/ management of FLSs/ISRs in patients with relapsing-remitting MS based on experiences from the randomized, placebo-controlled ADVANCE study of peginterferon beta-1a. Methods: ADVANCE investigators with a predefined number of enrolled patients were eligible to participate in a consensus-generating exercise using a modified Delphi method. An independent steering committee oversaw the development of two sequential Delphi questionnaires. An average rating (AR) of 2.7 or more was defined as consensus a priori. Results: Thirty and 29 investigators (ie, responders) completed questionnaires 1 and 2, respectively, representing 374 patients from ADVANCE. Responders reported that the incidence/duration of FLSs/ISRs in their typical patient generally declined after 3 months of treatment. Responders reached consensus that FLSs typically last up to 24 hours (AR = 3.17) and have mild/moderate effects on activities of daily living (AR = 3.34). Patients should initiate acetaminophen/nonsteroidal anti-inflammatory drug treatment on a scheduled basis (AR = 3.31) and change the timing of injection (AR = 3.28) to manage FLSs. Injection-site rotation/cooling and drug administration at room temperature (allAR ≥ 3.10) were recommended for managing ISRs. Patient education on FLSs/ISRs was advocated before treatment initiation. Conclusions: Delphi responders agreed on the management strategies for FLSs/ISRs and agreed that patient education is critical to set treatment expectations and promote adherence. [ABSTRACT FROM AUTHOR]

The article describes the microbiology, epidemiology, immunology, and pathology of progressive multifocal leukoencephalopathy (PML), its changing clinical and athologic spectrum, advances in the understanding of the pathogenesis of PML, and its relevance to physicians treating patients with rheumatic disorders. The natural history of PML, a serious, and usually fatal demyelinating disease that occurs in severely immunosuppressed patient populations, is poorly defined. The key element for survival in PML is reversal of the immuniosuppressed state.

Leukocyte trafficking to the central nervous system (CNS), regulated in part by chemokines, determines severity of the demyelinating diseases multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). To examine chemokine receptor CX3CR1 in EAE, we studied CX3CR1GFP/GFP mice, in which CX3CR1 targeting by insertion of Green Fluorescent Protein (GFP) allowed tracking of CX3CR1+ cells in CX3CR1+/GCP animals and cells destined to express CX3CR1 in CX3CR1GCP/GFP knockouts. NK cells were markedly reduced in the inflamed CNS of CX3CR1-deficient mice with EAE, whereas recruitment of T cells, NKT cells and monocyte/ macrophages to the CNS during EAE did not require CX3CRI. Impaired recruitment of NK cells in CX3CR1GCP/GFP mice was associated with increased EAE-related mortality, nonremitting spastic paraplegia and hemorrhagic inflammatory lesions. The absence of CD1d did not affect the severity of EAE in CX3CR1GFP/GFP mice, arguing against a role for NKT cells. Accumulation of NK cells in livers of wild-type (WT) and CX3CR1GFP/GFP mice with cytomegalovirus hepatitis was equivalent, indicating that CX3CL1 mediated chemoattraction of NK cells was relatively specific for the CNS. These results are the first to define a chemokine that governs NK cell migration to the CNS, and the findings suggest novel therapeutic manipulation of CX3CR1 + NK cells. [ABSTRACT FROM AUTHOR]

The precipitating event(s) that triggers Wegener's granulomatosis (WG) is unknown. Cytokines, costimulatory molecules, and counterregulatory molecules control the quality and intensity of immune responses. Thus, they are relevant candidates for genetic studies of immune dysregulation in WG, the pathogenesis of which may be facilitated by multiple acquired and/or inherited factors. This study was undertaken to investigate possible genetic associations of various proinflammatory cytokines and CTLA‐4, a receptor for T cell inhibition, with WG. Using polymerase chain reaction–based DNA genotyping, we investigated the polymorphisms located in the genes encoding a variety of proinflammatory cytokines and CTLA‐4 in 117 American patients with WG and 123 ethnically matched healthy controls. Compared with controls, patients with WG had a significantly lower frequency of homozygosity for the shortest allele (designated allele 86) of the Ctla4 microsatellite polymorphism (AT)n located in the 3′‐untranslated region (3′‐UTR) of exon 3 (47.0% versus 69.9%; P = 0.0005). Significant differences between patients and controls in the allelic and genotypic frequencies of polymorphisms in the other cytokine and cytokine receptor genes studied (tumor necrosis factor α [TNFα], TNF receptor I [TNFRI], TNFRII, interleukin‐1β [IL‐1β], IL‐6) were not found.The Ctla4 (AT)n 86 allele has been previously demonstrated to be crucial for maintenance of normal levels of CTLA‐4 expression and balance between T cell activation and inhibition. Our results in American patients confirm findings from a Scandinavian cohort in which a positive association between WG and longer alleles of (AT)n in the Ctla4 3′‐UTR was demonstrated. Diminished frequencies of the most effective allele for CTLA‐4 expression may represent a WG‐related susceptibility mutation that accounts, in part, for increased T cell activation and clonal expansion in WG. Blockade of T cell costimulation using CTLA‐4Ig might be a useful therapeutic intervention, providing an alternative or complementary approach to conventional treatment with immunosuppressive agents. [ABSTRACT FROM AUTHOR]

Examines single nucleotide polymorphisms in the cytotoxic T lymphocyte associated protein 4 (CTLA-4) gene. Frequencies of allele G and genotype G/G; CTLA-4 gene in myasthenia gravis; Amino acid substitution.

An abstract of the article "Chemokine Receptor CXCR3: An Unexpected Enigma," by Liping Liuis and colleagues is presented.